Contains Nonbinding Recommendations
点。其它可能的问题应确定和调查。生产工艺的记录和文件应全部再检查一遍，以确定引起OOS结果的可能原因。
The records and documentation of the manufacturing process should be fully reviewed to determine the possible cause of the OOS result(s). 应对生产记录和文件做全面的审核以确认可能的OOS原因。
A full-scale OOS investigation should consist of a timely, thorough, and well-documented review. A written record of the review should include the following information. 一个全面的OOS调查应包括及时的、彻底的及记录完整的审核。审核的书面记录应包括下述信息：
1. A clear statement of the reason for the investigation. 明确说明调查的原因。
2. A summary of the aspects of the manufacturing process that may have caused the problem. 对可能导
致问题产生的生产工艺的各方面的总结。 3. The results of a documentation review, with the assignment of actual or probable cause. 对文件和审
核结果，包括对实际原因和可能原因的归结。 4. The results of a review made to determine if the problem has occurred previously. 回顾以前生产中
是否曾发生相同问题的结果。 5. A description of corrective actions taken. 采取的整改措施。
If this part of the OOS investigation confirms the OOS result and is successful in identifying its root cause, the OOS investigation may be terminated and the product rejected. However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed (§
211.192). If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel. 如果在本部分OOS调查中，OOS结果被确认，且根本原因已被鉴别出，则OOS调查到此结束，该批次产品应被判定不合格。但是，扩展到别的批或产品不合格调查必须继续完成，别的批或产品可能与该结果有关(§ 211.192)。如果有物料在附加检验之后再经过加工，调查应包括适当的生产与质量控制人员的评论与签名。
OOS results may indicate a flaw in product or process design. For example, a lack of robustness in product
formulation, inadequate raw material characterization or control, substantial variation introduced by one or more unit operations of the manufacturing process, or a combination of these factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of the product or process be undertaken to ensure
reproducible product quality.8 OOS结果可能预示了产品或工艺设计的缺点。比如，产品浓度不够，原材料鉴定和控制不够，生产工艺中一个或多个操作单元引入过多的变量，或这些因素的结合，这些都可能是产品质量不稳定的原因。在这些情况下，有必要重新设计产品或工艺以确保产品质量。 B. Additional Laboratory Testing 附加化验室测试
A full-scale OOS investigation may include additional laboratory testing. A number of practices are used during the laboratory phase of an investigation. These include (1) retesting a portion of the original sample and (2) 8
OOS results might also be the result of the objectionable practice of making unauthorized or unvalidated changes to the manufacturing process.
Contains Nonbinding Recommendations
resampling. 一个全面的OOS调查可能包括附加的实验室检验。在调查的实验室阶段，要用到很多规范。这些包括（１）对一部分原样复验和（２）重新取样。
1. Retesting 复测
Part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid, it may be an additional weighing from the same sample composite prepared for the original test. 部分调查可能包括一部分原样的复验。用于复验的样品应该是最初收集检验的、出现OOS结果的样品均质物料的一部分。如果是液体，可以是液体成品的原始单位或液体成品的混合物。如果是固体，可以是分析员制备的相同混合物的额外的称量。 Situations where retesting is indicated include investigating testing instrument malfunctions or to
identify a possible sample handling problem, for example, a suspected dilution error. Decisions to retest should be based on the objectives of the testing and sound scientific judgment. It is often important for the predefined retesting plan to include retests performed by an analyst other than the one who
performed the original test. A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst. 原样复验旨在调查检测设备故障或确定样品处理上可能存在的问题，例如可疑的稀释错误等。决定复验应依据检验的客观和合理的科学判断。复验计划非常重要的一点是原样复验必须由另一名分析员执行，而不是原先的分析员执行。第二个分析员至少和第一个分析员一样有经验和有资格。
The CGMP regulations require the establishment of specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms (§ 211.160). CGMP要求建立规范，标准，取样计划，检验程序和其它实验室控制体制(§ 211.160)。
FDA inspections have revealed that some firms use a strategy of repeated testing until a passing result is obtained, then disregarding the OOS results without scientific justification. This practice of “testing into compliance” is unscientific and objectionable under CGMPs. The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound principles. The number of retests should not be adjusted depending on the results obtained. The firm's predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated. If the results are unsatisfactory at this point, the batch is suspect and must be rejected or held pending further investigation (§ 211.165(f)). Any deviation from this SOP should be rare and done in accordance with § 211.160(a), which states that any deviations from written specifications, sampling plans, test procedures, or other laboratory control
mechanisms shall be recorded and justified. In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QCU) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data. FDA检查显示，有些公司重复检验直到得到满意的结果，然后剔除没有科学依据的OOS结果。按照CGMPs检验至合格是不科学和不充许的。一个样品复验的最多次数应事先在SOP明确规定。不同的检验方法允许复验的次数可能不同，但应遵守科学合理原则。复验次数不能根据结果调整。公司的预先确定的复验程序应包括一个点，在这个点检验终止和进行批评估。如果在这个点结果不满意，则怀疑批，批不合格或待进一步调查(§ 211.165(f))。按照§ 211.160(a)不应背离SOP，§ 211.160(a)规定，任何背离书
Contains Nonbinding Recommendations
面规定，取样计划，检验程序或其它实验室控制制度应予记录和证明是正当的。在这种情况下，在复验前，应准备规程（由质量管理部门批准）描述附加的检验并明确提出数据的科学和／或技术的处理。
In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. All original data should be retained, however, and an explanation recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory
comments. (See section III of this guidance for more details on a laboratory investigation.) 在明确确定了实验室错误的情况下，原样复验结果合格，再检验结果将取代最初检验结果。应保留所有原始数据，但也应有解释性的记录。应该保留最初结果注明测定结果无效，在OOS调查记录上应有相关人员的签名、日期的标明，并应包括对错误的讨论和主管的注释。(详见本指南第三部分III实验室调查)
If no laboratory or calculation errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported 9 and considered in batch release decisions. 首次检验时若没有实验室错误或统计错误发生，就没有科学基础使原来的OOS结果无效，使复验结果通过。所有的检验结果，通过的和可疑的，都应有报告，在批放行中考虑。 2. Resampling 重新取样
While retesting refers to analysis of the original, homogenous sample material, resampling involves analyzing a specimen from any additional units collected as part of the original sampling procedure or from a new sample collected from the batch, should that be necessary. 重新取样指对已出现不合格结果的样品，按规定的取样规程，从同一批号样品中重新另取的第二组样品，供另外增加化验使用。目的是调查样品可能存在的问题。
The original sample from a batch should be sufficiently large to accommodate additional testing in the event an OOS result is obtained. In some situations, however, it may be appropriate to collect a new sample from the batch. Control mechanisms for examination of additional specimens should be in
accordance with predetermined procedures and sampling strategies (§ 211.165(c)). 同一批的原始的样品应有足够的量，万一出现OOS结果时以供附加的检验。但有的情况下，也可以从同一批中收集新的样品。附加样的检验控制应按照原先确定的程序和取样方法(§ 211.165(c)。
When all data have been evaluated, an investigation might conclude that the original sample was prepared improperly and was therefore not representative of the batch quality (§ 211.160(b)(3)).
Improper sample preparation might be indicated, for example, by widely varied results obtained from several aliquots of an original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was
inherently inadequate, a new accurate sampling method must be developed, documented, and reviewed and approved by the QCU (§§ 211.160 and 211.165(c)). 对所有的数据评估，调查的结论可能是原来
9
In other words, all data are reported in, for example, quality control reports, batch records, Certificates of
Analysis, in accordance with §§ 211.188 and 211.192. 换而言之，所有数据报告，如质量检测报告，批报告，分析报告应符合211章188和211章192的要求。
Contains Nonbinding Recommendations
的样品配制不当，所以不具有批质量的代表性(§ 211.160(b)(3)。这可由多种情形判定，如对原样不同部分进行检测，结果大范围波动（确定分析操作没有错误后）。重新取样应按照检测原样所使用的取样方法进行。若调查确定了原来的取样方法不正确，则须开发一个新的正确方法，并由QCU批准颁布实施。(§§ 211.160和211.165(c))
C. Reporting Testing Results 报告测试结果
Practices used in reporting and interpretation of test results include (1) averaging and (2) outlier tests. 对检验结果的报告和解释包括取平均值和异常结果检测。
1. Averaging 平均值
There are both appropriate and inappropriate uses of averaging test data during original testing and
during an OOS investigation: 在原始检测和OOS调查中，平均值可能会被正确使用，也可能会被误用。
a. Appropriate uses 正确使用
Averaging data can be a valid approach, but its use depends upon the sample and its purpose. For
example, in an optical rotation test, several discrete measurements are averaged to determine the optical rotation for a sample, and this average is reported as the test result. If the sample can be assumed to be homogeneous, (i.e., an individual sample preparation designed to be homogenous), using averages can provide a more accurate result. In the case of microbiological assays, the U.S. Pharmacopeia (USP) prefers the use of averages because of the innate variability of the biological test system. 取平均值可能是一个好的方法，但这取决于样品及其目的。例如，在比旋的检测中，几次独立检测得到的数据被取平均值作为一个样品的比旋。如果该样品被假定是均一的，（也就是说一个独立制备的样品假定是均一的）取平均值可以提供一个更准确的结果。在微生物含量测试中，美国药典倾向于取取平均值，因为生物检测系统本身具有不稳定性。
It should be noted that a test might consist of a specific number of replicates to arrive at a result. For instance, an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot, and from multiple full analyses of the same homogenous sample. The use of replicates to arrive at a single reportable10 result, and the specific number of replicates used, should be specified in the written, approved test method. Acceptance limits for variability among the replicates should also be specified in the method. Unexpected variation in replicate determinations should trigger remedial action as required by § 211.160(b)(4). If acceptance limits for replicate variability are not met, the test results should not be used. 这里应该注意的是，一次检验可能由一定的平行测定得到一个结果。比如，HPLC检验结果是由同一溶液的一组连续的，平行的进样的峰值平均得来的（通常是2或3）。这种测定是一次检验一个结果。这与一批中不同部分的分析明显不同，也与同一均质样品的多元全面分析不同。平行测定以得到最终结果，和平行测定的次数，应在书面的经批准的检验
10
The term reportable result as used in this document means a final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the
original sample.术语“可报告的结果”当用于本文中时，表示一个最终分析结果。该结果应是对一个原始样品，严格按照书面批准的检验方法进行完整的检验并计算所得的结果。
Contains Nonbinding Recommendations
方法中明确规定。平行测定中变化范围也应在方法中明确规定。按§ 211.160(b)(4)要求，平行测定中意料外的变化要采取矫正措施。如果不符合平行测定范围，检验结果不能用。
In some cases, a series of complete tests (full run-throughs of the test procedure), such as assays, are part of the test method. It may be appropriate to specify in the test method that the average of these multiple assays is considered one test and represents one reportable result. In this case, limits on
acceptable variability among the individual assay results should be based on the known variability of the method and should also be specified in the test methodology. A set of assay results not meeting these limits should not be used. 有时，检验方法可能包括若干完整的单个检验项目，如含量。此时应该在检验方法中明确说明数次检验结果的平均值作为一个检验结果报告。这时，各结果之间的允许的变动性应在方法中明确表述。如果一系列结果达不到该要求则不应取用。
These appropriate uses of averaging test data should be used during an OOS investigation only if they were used during the original testing that produced the OOS result. 仅仅当在产生OOS结果的原始检验中使用此平均值时，该平均值才会在OOS调查中被采用。 b. Inappropriate uses 不正确使用
Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard
deviation) is reported with the individual unit dose test results. 用平均法有掩蔽单个数据差异的弊端。由于这个原因，所有单个数据差异通常应单独报告。在检验方法中明确适用平均法的，平均结果可以做为检验结果。在一些情况下，报告变异结果的统计学处理。例如，在剂型含量均匀度的检验中，报告标准偏差（相对偏差）和单个剂型的检验结果。
Averaging can also conceal variations in different portions of a batch, or within a sample. For example, the use of averages is inappropriate when performing powder blend/mixture uniformity or dosage form content uniformity determinations. In these cases, testing is intended to measure variability within the product, and individual results provide the information for such an evaluation. 平均值可能会掩盖同一批中或同一样品中质量的不均一性。例如，当检验粉末混合均一性，或制剂含量均一性性时对数据进行平均是不合适的。在这种情况下，检测的目的就是要测试产品的均匀性质，单个的检测结果才可以为这样的评价提供信息。
In the context of additional testing performed during an OOS investigation, averaging the result(s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by the QCU, which is responsible for approving or rejecting, e.g., drug products,
in-process materials (§ 211.22) 在OOS调查的附加检验中，平均最初检验的结果，加快调查和复验或得到重新取样的结果，是不适当的，因为它掩蔽了各个结果之间的差异。当出现一些是OOS结果而其它结果的符合规定时，这些数据的平均尤其会造成误解。实验室提供所有单个结果非常重要，这些结果用于QCU评估和考虑，QCU负责批准或否定，如药品，在制品(§ 211.22)。
相关推荐：
loading